1, 1-bis (trihalo-methyl)-1,3-glycols

ABSTRACT

Typical is Alpha -((2-hydroxy-1-methyl-3,3,3-trifluoro-2trifluoromethyl)propyl) benzyl alcohol useful in riot control.   D R A W I N G

United States Patent Carl M. Langkammerer Wilmington, Del.

Nov. 16, 1967 Dec. 14, 1971 E. I. de Nemours and Company Wilmington, Del.

Original application May 7, i966, Ser. No. 551,844. Divided and this application Nov. 16, 1967, Ser. No. 684,601

inventor Appl. No. Filed Patented Assignee 1, 1-818 (TRlllALO-METHYL)-1,3-GLYCOLS 4 Claims, No Drawings [56] References Cited UNITED STATES PATENTS 3,121,121 2/]964 Lindsey et al 260/633 3,323,984 6/1967 Szabo 260/347. 8

Primary Examiner- Leland A. Sebastian Attorney-Herbert W. Larson ABSTRACT: 1,3-substitutedglycols of the formula:

wherein R is hydrogen, alkyl, alken l, naphthyl, thlenyl,

furyl, henyl or substitute phenyl; R is by rogen or alkyl; R and R can be joined; X and Z are separately trifluoromethyl or chlorodifiuorornothyl. I Typical is a-[(2-hydroxy-l-methy|-3,3,3-trifluoro-2- trifluoromethyi)propyl] benzyl alcohol useful in riot control.

SUMMARY OF THE INVENTION purpose of causing disability.

THE INVENTION The compounds of this invention possess the following structural formula:

' OII ll X R is hydrogen, alkyl and one through four carbon atoms, al-

kenyl of two through four carbon atoms, naphthyl, thienyl, furyl or A is hydrogen, fluorine, chlorine, bromine, nitro, sult'onylamide, methyl, methoxy or phenyl;

D is hydrogen, fluorine, chlorine, bromine, nitro, sulfonylamide, methyl or methoxy;

E is hydrogen, fluorine, chlorine, bromine, nitro, sulfonylamide, methyl or methoxy;

X is trifluoromethyl or chlorodifluoromethyl;

Z is trii'luoromethyl or chlorodifluoromethyl;

R is hydrogen or alkyl of one through seven carbon atoms with the limitation that unless R is hydrogen the alkyl is one through three carbon atoms; and R and R can be cyclopentane, cyclohexane, cyclohexene, cyclododecane, tetrahydronaphthalene and norbomane.

The compounds of formula (1) wherein R is hydrogen or methyl are preferred because of high incidence of animal disability at low-dose rates.

Use

The compounds described above cause irritation to animals, affecting the eyes and upper respiratory tract. In aerosols the compounds could be used in riot control, rodent control or burglar alarm systems.

Some of the compounds of the present invention such as 2- (2-chloro-2,2-difluoro- 1 -hydroxyl -trifluoromethyl)-ethylcyclopentanol produce desirable analgesic effects in warm blooded animals if administered in a controlled pharmaceutical dose.

Preparation Compounds of the present invention are made employing a Meerwein-Pondorff process and using aluminum isopropoxide in isopropanol by reducing the adducts of hexafluoroacetone, or other halogenated acetones with aldehydes and ketones having a CH, group in positions alpha to the carbonyl group. The starting materials have the following structural formula:

wherein R, R, A, D, E, X and Z have the same meaning as above.

Compositions Compounds of this invention can be administered alone but are generally contained in a composition with a pharmaceutical carrier or diluent selected on the basis of the chosen route of administration and standard pharmaceutical practice. if the chosen route of administration is orally, the compounds can be administered in the form of tablets or capsules containing such excipients as starch, milk, sugar, clays and the like. Compounds can also be administered orally in the form of elixirs or oral suspensions containing coloring and flavoring agents.

It administered parenterally, the composition can take the form of sterile aqueous solutions containing solutes such as saline, or glucose in suflicient quantity to make the solution isotonic. For intramuscular administration, compositions of the compounds of this invention can be prepared in and] base such as peanut or sesame oil.

If administered as a vapor or spray application through the mouth or nasal passages a composition will contain some acceptable liquid such as water, acetone, or alcohol.

Dosage The amount of active ingredient in the compositions will vary from 0.005 percent to percent by weight or even higher. Exact concentration of active ingredient will depend on the mechanism used for administration and will be easily understood by one knowledgeable in phannaceutical application rates. The effective pharmaceutical dose of an intravenous treatment is 0.5 to 5 milligrams of active compound per kilogram of body weight of the animal recipient. Amounts of over 56 milligrams per kilogram of body weight are required to kill 50 percent of the animal recipients.

An effective pharmaceutical dose of an inhalation treatment is 0.5 to 2 milligrams per liter of air at exposure of 1 minute. More than milligrams per liter of air at an exposure of 1 minute is required to kill 50 percent of the animal recipients.

The following additional examples are provided to more clearly set forth the invention.'All "parts" are by weight unless otherwise indicated.

EXAMPLE 1 A pressure vessel made of Hastelloy C is evacuated, cooled in a liquid nitrogen bath, and charged with 70 parts of hexafluoroacetone (seven parts excess over an equimolar quantity) and 50 parts of propiophenone. The pressure vessel is sealed, heated to l60 C. during 2 hours, held at this temperature for 4 hours, then held at 180 C. for 4 hours, cooled and vented. The resulting ll 1 g. of yellow liquid is distilled to give 85.6 pans (77 percent yield) of 2-methyl-3-hydroxy-l-phenyl 4,4,4-trit'luoro-3-trifluoromethyll -butanone boiling at 7072 C. at 0.06 mm. of mercury; n,,l .44 l 6.

Anll.Cslc'd.forC,,l-l F.0,: c 4&0; H 3.: Found: C 48.2; H 3.5

Thirty parts of 2-methyl-3-hydroxy-l-phenyl-4,4,4- trifluoro-3-trifluoromethyl-l-butanone, 30.3 parts of aluminum isopropoxide and parts of dry isopropanol is placed in a flask equipped with a magnetic stirrer and attached to a Vigreaux distillation column and a receiver, the whole apparatus being protected from atmospheric moisture by a CaCl, tube. A liquid consisting of acetone and isopropanol is distilled off slowly during 16 hours and the remainder removed by vacuum. The residue is warmed with 54 parts concentrated hydrochloric acid and 250 parts of water. It is extracted with ether. The ether extract is dried with anhydrous magnesium sulfate, evaporated and the residue vacuum distilled. Twenty-one parts (70 percent yield) of a-[(2- hydroxyl -methyl-3 ,3 ,3-trifluoro-2-trifluoromethyl )propyl 1b enzyl alcohol are obtained, boiling at 98-l0l C. at a pressure of 0.6 mm. of mercury; n l .4438.

14 mm. ofmercury n,,l .3597.

Anal. Cslc'd. forC H F.O,: c 47.6; H 4.7l Found: c 40.5; H 4.7

Found: C 47.4; H 4.2 5

Twenty-six and six-tenths parts of 1,1,l-trifluoro-2-hydrox- Mice are treated y wow! exposure to the test compound y-S,5-dimethyl-2-trifluoromethyl-4-hexanone, 30.3 parts of in the -"B manner: compound is adminilwl'ed an aluminum isopropoxide and 150 parts of dry isopropanol are MI B I in 8 liter h mb The Q P chambfl' placed in a flask equipped with a magnetic stirrer and attached beuj" wel'anebuliul' mum thIOIIBh lhe 10 to a Vigreaux distillation column and a receiver protected floor are P for 5 minute! to 200 from atmospheric moisture with a calcium chloride tube. A micrograms H The p i8 dmlved in acetone liquid consisting of acetone and isopropanol is distilled off an ng a P of 20 Second! the compound is p y p slowly during 48 hours and the remainder removed by vacuum into the chamber. No further air is transferred into or out of distillation. The residue is warmed with a solution of 54 parts the chamber during the 5 minute exposure. of concentrated hydrochloric acid, cooled, extracted with After this exposure, irritant activity is observed in all mice ether, and the ether extract is dried with anhydrous magnesiexposed, but not in controls exposed to acetone alone. irritant um sulfate, evaporated and the residue distilled. Twenty-one activity can be described as the presence of one or more of the parts (75 percent yield) of 5,5-dimethyl-1,1,l-trifluoro-2- following reactive signs: trifluoromethyl-2,4-hexanediol are obtained with a boiling Hype mi oft-he 11080, 0 n tail point of 98-l00 C. at a pressure of 18 mm. of mercury; m.p. Salivation 49-5l C. Pmsis r F c 40 a H s 2 Dyspnea Ammo-k d m C'H" '0" Found: c 40:3; H 5:2 Decreased locomotor activity Blinking Squirrel monkeys are exposed to the test compound in the Hunched posture following manner: the compound is dissolved in methylene Face pawing. chloride, forming a colorless solution. The solution is forced Gerbils are treated to the test compound by exposure in a through a nebulizer, and thence to a turbulence bulb, where 16 liter static chamber in the following manner: the compound the compound forms particles distinct from the vapor of the is dissolved in methylene chloride. The resulting colorless solvent. Both solute and solvent vapors are blown into a 50 solution is sprayed into the chamber through a port in the botliter chamber containing two monkeys. The animals are extom, animals being maintained around the entrance port. The posed to a concentration of 2000 micrograms for l minute, spray impinges on the top of the chamber, then slowly settles with constant flow of compound maintaining this concentradown on the gerbils in the form of a vapor. The exposure time i yn mi chamber)- is 1 minute. A concentration which shows irritant activity is A! the end of the QXPOSUTB, the monkeys are removed from 2000 micrograms. The gerbils are removed from the chamber th hamber and caged in well-ventilated quarters. Characat the end of 1 minute exposure. Characteristic symptoms in tefiltic 8i8n8 in the chambers during exposure the gerbil after exposure to irritants are the following: are the following:

Abnormal gait, consisting of rubbing the nose on the floor Saul/85" while walking about (shovelnosing) Face pawing Ptosis Laclimation Face pawing Dy p Dyspnea- EXAMPLES 3-30 i are treated a sumlar to gerbils and Show The following compounds are made in the manner of the follovimgsympmms m addmon to the above: compounds of examples 1 and 2 by substituting the api propriate starting materials of the following formula. The i f meaning of R, R, x and z is found in table I. Plloerectlon s Hyperactivity. O O O H X R- I-R' X M7, R(IB(I}(IIOH r EXAMPLE 2 I 1's i u (l) (H) (lll) 011 ll x The Hastelloy C pressure vessel of example 1 is evacuated, l cooled in liquid nitrogen, and charged with l 15 parts of hexafluoroacetone and 61 parts of pinacolone (an excess of eight II R Z parts of hexafluoroacetone above an equimolar quantity). The v pressure vessel is sealed, heated to 160 C. during 2 hours, T held at this temperamfc 8 how's, cooled and wdh The compounds are formulated and applied to animals in like 174 g. of liquid obtained is distilled to give 154 parts (94 permanner to provide like results. cent yield) of l,l,l-trifluoro-2-hydroxy-5,5-dimethyl-2- The properties and analytical data for the compounds of extrifluoromethylflhe xanone with a boiling point of 52 C. at amples 3-30 are presented in table ll.

TABLE I Example I II Number R R x z III 1V 3 H n-CrH CFS CF; CmHmFoOz 1,1,l-trifiuoro-Z-trifluoromethyll-3-hydroxymethyl-2-0ctall0l. 4 CH3 H CF; CF; CQHBHBOZ 1,1,htrifiuoro-Q-trifiuoromethyl-2,4-pendanediol. 5 (CH;)2C=CH H CF; CFa CQHIUFQOZ l-chloro-l,1-difiu0ro-6-methyl-2-trifluoromethyl-5-h0ptalle-2A- Same as above H CFgCl CF; CnHmClFsO 1,gifirifluoro-ltrifiuoromethyl-5-heptane-2,4-diol.

5 g CFs C a CllHaFgOz 1-pheny1-4,4,4-trifiuoro-3-trifiuoromethyl-l ,3-butanediol.

nHsChFl 2,3,4tetrahydro-1-naphth a-T etralone 2-(2,2,.l-trifluoro-l-hydroxy-litrifiuoromethyl) cthyH,

TABLE II-Oontlnued RmmncHR'O(GF,X)(CF.Y)0II compound Alllliyhtlhl v nlculuiml Found Ex mple e V.V. V.. ms-

., s .7 No. IV Properties 0 II Cl N S 0 ll (ll N 24 U N,N-diethyl-3[(1,8-dihydroxy-4,4,4- bo-,,193- 42.5 4.5 3.3 43.5 4.3 3.x

trifluoro-3-trlfiuoromethyl)butyl]- benzenesulfonamide.

fi-phcnyl-l,LI-trifluoro-Z-trlfiuoro b... 1067 49.7 3.3 50- mothyl-5-hexene-2,4-d1ol. 26 5-phe 0xy-1,1,l-trifluoro-Z-trlfiuoroh 101-5, 45.2 3.8 1 V s methyl-2,4-pentanediol. my 1.4476. l7 4-chloro4,4-difiuoro-3-(ehlorodifluoro- 1 123-s 30. 4 3. 0 22. 5 a0. 3

methyl)-1-furyl-1,3-butanedlol. i 28 4-chloro-3-(chlorodifium-omerh l)4,4- 1, 118, 33.0 2. 4 21.7 q .7 33. n 2. 4 22. 6

difluoro-l-(2-thienyl)-1,3-butanediol. in) 1.4972 2-methyl-1-(2-tl1ienyl)-4,4,4-trifit10r0-3- Do 92-3", 39. 0 3.3 V v 10.4 321.1 3. 4 10. e1

trlfluoromethyl-l,3-butanediol. no 1.4480 30 2-cthyl-l-(2-thienyl)-4,4,4-trlt'luor0-3- 1 78-81 47.0 3.7 41.8 3. u l

- tnfluoromethyl-l,3-butancdiol.

EXAMPLE 3] What is claimed is: Y A Hastelloy C pressure vessel is evacuated, cooled in liquid A compound of formula: nitrogen and charged with 63 parts of cyclopentanone and 1 H X 182.5 parts of monochloropentafluoroacetone. The pressure R s I vessel is sealed, heated to 160 C. during 2 hours and held at l I I J this temperature for 10 hours. The 238 parts of liquid obwherein H R tained after coolin and ventin is distilled to ive 172 arts g 8 g p R is selected from the group consisting of hydrogen, alkyl of (64 percent yield) of 2-(2-chloro-2,2-d1fluoro-l-hydroxy-lflu f ho to am 1 f w u trifluoromethyl)-cthylcyclopentanone with a boiling point of g a our-car g? 1.? ough 37 C. at a pressure of 0.07 mm. of mercury; N 1 .4 Q5 8. 7 our car H atoms nap y ry an A Analysis Calc'd-forCJi-CIEQ: C 36.0; H 3.0;

Cl 13.: Found: C 35.5; H 3.2;

I) E 2-(2-Chloro-2,2-difluoro-l-hydroxy-l-tritluoromethyl)- ethylcyclopentanone (26.7 parts), 30.3 parts of aluminum A is selected f he group fini f hydmgem mopmpoxfde and P pan8 of WW are chug into a fluorine, chlorine, bromine, nitro, sulfonylamide, methyl flask equipped with a magnetic stirrer and attached to a methoxy and Pheny]; Vigreaw distillation column and a rece|ver protected st- D and E are m ulccmd fr the poup consisting f mosphenc moisture with a calcium hl tube- L'qmd hydrogen, fluorine, chlorine, bromine, nitro, sulfonyla (acetone and tsopropanol) is distilled off slowly for 6 hours mid, methyl and m and remarnden removed by vacuum distillation. The x and Z are separately deem; f the group consisting f residue is warmed with a solution of 54 parts of concentrated trifluowmthfl and chlomdifluommethyk hydrochloric acid, cooled and extracted with ether. The ether is selected from the group confining of hydrogen and extract is dried, evaporated and the residue distilled. A 69 peralkyl of one through even carbon atoms with the mini. 185 pm) 0f P' f tion that unless R is hydrogen the alkyl can have only one l-tnfluoromethyl)ethylcyclopentanol was obtained with a through carbon atoms; and R and R' an joined w boxing point of 86 C. at a pressure of 0.75 mm. of mercury, form radical when! from the group comma"; f so cyclopentane, cyclohexane cyclohexene, cyclododecane,

tetrahydronaphthalene and norbornane. Ami) CIHIFIF-W C 3 7 2. A compound of claim 1 which has the formula:

Found: C 34.5, H 3 7 011 II x EXAMPLES 32-36 (L lt C()ll. The following compounds are made in the manner of 2-(2- l chloro-2,2-difluoro- 1 -hydroxy- 1 -trifluoromethyl)-ethylcyclopentanol of examples 31 by substituting the appropriate wherein starting materials for the cyclopentanone of example 31. R is selected from the group consisting of hydrogen, alkyl of TABLE III Analyses Calculated Found Example No. Starting material Compound Properties Formula C H C H 32 Cyc1opentan0ne... 2-(2,2,2trifluorol-hydroxy-l-trifluoromethyl)ethylb 75, CaHtoFoOz 38. 2 0

cyclopentanol. 1213 1.3854 3 Cyclododecanone-.. trans-2-hyifioxyia,a-bis(trlfluor0methyl)cyclodode- M I. 2 C15 z4Fo0z 51. 4 J I-0 cane-me 3.110 ciS-Z-hgdrogry-ag-bis(trifluoromethyl)cylcododecane- M P. 87-91 C15H24Fu02 51.4 6. 9 5.13 6.9

me flIIO 34 s p r 6-(2,2,2-trlfiuoro-l-hydroxy-l-trifluoromethyllethyl-3, 0 86-9 CzlI'ImFBOt 47. 0 5.2 7.0 2

5,5-trimethyl-2-cyclohexen-1-ol. up 1.4195 35 m o e 2-[(1-hydroxy-2,2,2-trifluoro-l-trifluoromethyl)ethy1]-6- b '1 904 C13H20F602 48. 4 3 3 8 isopropyl-3-methyl-cyc1ohexan0l. 36 1 4 M P, 87-9 CnHnFaO: 50. l] 3- 3 W- 3 8 9 I 10 one through four carbon atoms, alkenyl of two through fluorine, chlorine, bromine, nitro, sulfonylamide, methyl,

four carbon atoms, naphthyl, thienyl, fury], and methoxy and phenyl;

- D and E are separately selected from the group consisting of hydrogen, fluorine, chlorine, bromine, nitro, sulfonylamide, methyl and methoxy;

X and Z are separately selected from the group consisting of trifluoromethyl and chlorodifluoromethyl.

3. A compound of claim I which is a-[(2-hydroxy- 1 -methyl- D E 3,3,3-trifluoro-2-trifluoromethyl )propyllbenzyl alcohol.

4. A compound of claim 1 which is 5,5dimethyl-l,l,ltrifluoro2-trifluoromethyl-2,4-hexanediol.

A is selected from the group consisting of hydrogen, s -ow s NH Viz/s 

2. A compound of claim 1 which has the formula: wherein R is selected from the group consisting of hydrogen, alkyl of one through four carbon atoms, alkenyl of two through four carbon atoms, naphthyl, thienyl, furyl, and
 3. A compound of claim 1 which is Alpha -((2-hydroxy-1-methyl-3,3,3-trifluoro-2-trifluoromethyl)propyl)benzyl alcohol.
 4. A compound of claim 1 which is 5,5-dimethyl-1,1,1-trifluoro-2-trifluoromethyl-2,4-hexanediol. 